Iron-catalyzed 2-arylbenzoxazole formation from o-nitrophenols and benzylic alcohols

Article abstract of DOI:10.1021/ol300937z

The iron-catalyzed 2-arylbenzoxazole formation from o-nitrophenols and benzylic alcohols using hydrogen transfer is described. Various 2-arylbenzoxazoles were selectively obtained in good to excellent yields. The reaction tolerated a wide range of functionalities. The alcohol oxidation, nitro reduction, condensation, and dehydrogenation were realized in a cascade without external reducing reagent and oxidant.

Full text of DOI:10.1021/ol300937z

ORGANIC
LETTERS
2
012
Vol. 14, No. 11
722–2725
Iron-Catalyzed 2-Arylbenzoxazole
Formation from o-Nitrophenols and
Benzylic Alcohols
2
Mingyue Wu, Xiong Hu, Juan Liu, Yunfeng Liao, and Guo-Jun Deng*
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
gjdeng@xtu.edu.cn
Received April 11, 2012
ABSTRACT
The iron-catalyzed 2-arylbenzoxazole formation from o-nitrophenols and benzylic alcohols using hydrogen transfer is described. Various
-arylbenzoxazoles were selectively obtained in good to excellent yields. The reaction tolerated a wide range of functionalities. The alcohol
oxidation, nitro reduction, condensation, and dehydrogenation were realized in a cascade without external reducing reagent and oxidant.
2
Aryl-substituted benzoxazoles are common building
blocks for the synthesis of pharmaceuticals, natural prod-
ucts, functional materials, and agrochemical compounds.
These compounds have been extensively studied for their
benzoxazoles have been successfully synthesized by direct
CꢀH activation and subsequent CꢀC bond formation
3
with aryl halides, arylsilanes, aromatic carboxylic acids,
4
5
6
aryl boronic acids, sodium sulfinates and aryl triflates,
7
1
8
biological and therapeutic activities. Consequently, devel-
and even arene CꢀH bonds via double CꢀH activations.
opment of efficient methods for rapid construction of aryl-
substituted benzoxazoles has stimulated considerable in-
terest. Recently, the activation of CꢀH bonds has received
much attention for the straightforward construction of
The conventional methods for the synthesis of these
important compounds typically involve two approaches.
One is the metal-catalyzed intramolecular cyclization of
9
o-haloanilides or their analogues (Scheme 1, a). The
2
CꢀC and Cꢀhetero bonds. Various aryl-substituted
second approach mainly involves the condensation of 2-
aminophenol with either a carboxylic acid derivative under
strong acid/high temperature conditions or an aromatic
(
1) (a) Zirngibl, L. Antifungal Azoles: A Comprehensive Survey of
Their Structures and Properties; Wiley-VCH: Weinheim, 1998. (b)
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. Comprehensive Heterocyclic
Chemistry III, Vol.1; Pergamon: Oxford, 1999. (c) Katritzky, A.; Pozharskii,
A. Handbook of Heterocyclic Chemistry, 1st ed.; Pergamon: Oxford, 2003.
(4) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2010, 49, 2202.
(
2) For selected reviews on CꢀH functionalization, see:(a) Dyker, G.
(5) Zhang, F.; Greaney, M. Angew. Chem., Int. Ed. 2010, 49, 2768.
(6) (a) Guchhait, S.; Kashyap, M.; Saraf, S. Synthesis 2010, 1166. (b)
Liu, B.; Qin, X.; Li, K.; Li, X.; Guo, Q.; Lan, J.; You, J. Chem.;Eur. J.
2010, 16, 11836. (c) Ranjit, S.; Liu, X. Chem.;Eur. J. 2011, 17, 1105. (d)
Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.; Itami, K.
Angew. Chem., Int. Ed. 2011, 50, 2387.
Handbook of CꢀH Transformations: Applications in Organic Synthesis;
Wiley-VCH: Weinheim, 2005. (b) Yu, J.; Shi, Z. CꢀH Activation; Springer:
Berlin, 2010. (c) Goldberg, K. I.; Goldman, A. S. Activation and Functio-
nalization of CꢀH Bond; ACS Symposium Series 885; American Chemical
Society: Washington, DC, 2004.
(
3) For recent selected examples, see: (a) Turner, G.; Morris, J.;
(7) (a) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem, Int.
Ed. 2008, 48, 201. (b) Roger, J.; Doucet, H. Org. Biomol. Chem. 2008, 6,
169. (c) Ackermann, L.; Barfusser, S.; Pospech, J. Org. Lett. 2010, 12,
724. (d) Chen, R.; Liu, S.; Liu, X.; Yang, L.; Deng, G. J. Org. Biomol.
Chem. 2011, 9, 7675. (e) Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, J. S.
Chem.;Eur. J. 2011, 17, 13415. (f) So, C.; Lau, C.; Kwong, F. Chem.;
Eur. J. 2011, 17, 761.
Greaney, M. Angew. Chem., Int. Ed. 2007, 46, 7996. (b) Do, H.; Daugulis,
O. J. Am. Chem. Soc. 2007, 129, 12404. (c) S ꢀa nchez, R.; Zhuravlev, F.
J. Am. Chem. Soc. 2007, 129, 5824. (d) Lewis, J.; Berman, A.; Bergman, R.;
Ellman, J. J. Am. Chem. Soc. 2008, 130, 2493. (e) Canivet, J.; Yamaguchi,
J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (f) Zhao, D.; Wang, W.;
Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009,
4
8, 3296. (g) Huang, J.; Chan, J.; Chen, Y.; Borths, C.; Kyle, K.; Larsen,
(8) (a) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.;
You, J. J. Am. Chem. Soc. 2010, 132, 1822. (b) Han, W.; Mayer, P.; Ofial,
A. R. Angew. Chem., Int. Ed. 2011, 50, 2178. (c) Malakar, C.; Schmidt,
D.; Conrad, J.; Beifuss, U. Org. Lett. 2011, 13, 1378. (d) Wang, Z.; Li,
K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2011, 50, 5365.
(f) Gong, X.; Song, G.; Zhang, H.; Li, X. Org. Lett. 2011, 13, 1766.
R.; Margaret, M. J. Am. Chem. Soc. 2010, 132, 3674. (h) Shibahara, F.;
Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 46, 2471. (i) Shibahara,
F.; Yamaguchi, E.; Murai, T. J. Org. Chem. 2011, 76, 2680. (j) Yamamoto,
T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K.
Chem.;Eur. J. 2011, 17, 10113.
1
0.1021/ol300937z r 2012 American Chemical Society
Published on Web 05/23/2012

as the starting materials for the preparation of 2-arylbenzoxa-
zoles. There are few examples for 2-arylbenzoxazole for-
mation from 2-nitrophenols and aldehydes (or trimethyl
orthobenzoate) using large amount of metals as nitro group
Scheme 1. Different Pathways for the 2-Arylbenzoxazole
Formation
15
reductants. 2-Nitrophenols was also successfully coupled
with benzylic amines to give 2-arylbenzoxazoles under high
1
6
reaction temperatures (>200 °C).
Very recently, we and others developed various catalytic
systems for direct CꢀN bond formation from nitroarenes
1
7
18
and alcohols or cyclohexanones using the borrowing
1
9
hydrogen methodology (or hydrogen transfer). In this
process, nitroarenes were reduced in situ using the bor-
rowed hydrogen generated from the alcohol or cyclohex-
anone oxidation step. This method afforded a shortcut for
CꢀN bond formation using stable starting materials with-
out any external reducing reagent and oxidant. However,
noble catalysts such as ruthenium, palladium, or iridium
were used in most cases. The use of cheap and nontoxic
iron catalyst for CꢀN bond formation would be highly
2
0
desirable. Herein, we report an iron-catalyzed 2-arylben-
zoxazole formation from o-nitrophenols and benzylic
alcohols, affording the aryl-substituted benzoxazoles in
high yields (Scheme 1, c).
1
0
aldehyde under strong oxidative conditions (Scheme 1, b).
Recently, catalytic oxidative reactions using oxygen as the
terminal oxidant have received much attention. However,
these reactions require the use of large amounts of the
catalyst or excess base. To overcome these limitations,
Han et al. developed an aerobic oxidative synthesis of
We began our study by examining the reaction of
-nitrophenol (1a) and benzyl alcohol (2a) in toluene at
2
1
1
150 °C. When 2-nitrophenol reacted with 2.5 equiv of
benzyl alcohol in the absence of any catalyst, no desired
1
product 3a was obtained as determined by GC and H
2
-substituted benzoazoles catalyzed by 4-methoxy-TEMPO
1
2
using oxygen as the oxidant. Williams et al. developed
an iridium-catalyzed 2-arylbenzoxazole formation from
aldehydes and o-aminophenols even in the absence of
oxidant. Kobayashi et al. disclosed a supported Pt-
catalyzed aerobic oxidation of phenolic imines under very
1
mild conditions. In most cases, 2-aminophenols are used
NMR methods (Table 1, entry 1). Then various iron salts
were investigated for this reaction under similar reaction
conditions. FeSO Fe(NO ) , Fe O , and Fe (SO ) were
4
,
3 3
2
3
2
4 3
1
3
proved to be ineffective catalysts for this kind of transfor-
mation (entries 2ꢀ5). The desired product was obtained in
4
18% and 31% yields when ferrocene and Fe(acac) were
used (entries 6 and 7). The reaction yields could be further
3
(
9) For selected examples, see: (a) Evindar, G.; Batey, R. A. J. Org.
Chem. 2006, 71, 1802. (b) Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71,
261. (c) Itoh, T.; Mase, T. Org. Lett. 2007, 9, 3687. (d) Zou, B.; Yuan,
improved to 79% and 81% when 5 mol % of FeCl and
3
FeCl were employed (entries 8 and 9). Among the various
2
8
0
iron salts examined, dppf [1,1 -bis(diphenylphosphino)-
Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (e) Liu, F.; Ma, D.
J. Org. Chem. 2007, 72, 4884. (f) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem.
007, 72, 9329. (g) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665. (h)
Viirre, R.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452. (i)
Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411. (j) Ma,
D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int.
Ed. 2009, 48, 4222. (k) Saha, P.; Ramana, T.; Purkait, N.; Ali, M.; Paul,
R.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (l) Ueda, S.;
Nagasawa, H. J. Org. Chem. 2009, 74, 4272. (m) Wang, H.; Wang, L.;
Shang, J.; Li, X.; Wang, H.; Gui, J.; Lei, A. W. Chem. Commun. 2012,
ferrocene] was the most effective, and its use resulted in
the formation of 3a in 82% yield (entry 10). The choice of
solvents was crucial for this reaction. The use of NMP,
2
(15) (a) Hari, A.; Karan, C.; Rodrigues, W. C.; Miller, B. L. J. Org.
Chem. 2001, 66, 991. (b) Lee, J. J.; Kim, J.; Jun, Y. M.; Kim, B. H.; Lee,
B. M. Tetrahedron 2009, 65, 8821.
4
8, 76.
(16) Nishioka, H.; Ohmori, Y.; Iba, Y.; Tsuda, E.; Harayama, T.
Heterocycles 2004, 64, 193.
(
10) (a) Bernardi, D.; Ba, L. A.; Kirsch, G. Synlett 2007, 2121. (b)
Benedi, C.; Bravo, F.; Uriz, P.; Fernandez, E.; Claver, C.; Castillon, S.
Tetrahedron Lett. 2003, 44, 6073. (c) Riadi, Y.; Azzalou, R.; Lazar, S.;
Mamouni, R.; Haddad, M.; Routier, S.; Guillaumet, G. Tetrahedron
Lett. 2011, 52, 3492. (d) Bose, D. S.; Idrees, M. Synthesis 2010, 398.
(17) (a) Feng, C.; Liu, Y.; Peng, S. M.; Shuai, Q.; Deng, G. J.; Li, C.-J.
Org. Lett. 2010, 12, 4888. (b) Liu, Y.; Chen, W.; Feng, C.; Deng, G. J.
Chem. Asian J. 2011, 6, 1142. (c) Luo, J. Y.; Wu, M. Y.; Xiao, F. H.;
Deng, G. J. Tetrahedron Lett. 2011, 52, 2706. (d) Cui, X. J.; Zhang, Y.;
Shi, F.; Deng, Y. Q. Chem.;Eur. J. 2011, 17, 2587. (e) Zanardi, A.;
Mata, J. A.; Peris, E. Chem.;Eur. J. 2011, 47, 6981. (f) Cano, R.;
Ram oꢀ n, D. J.; Yus, M. J. Org. Chem. 2011, 76, 5574. (g) Tang, C. H.; He,
L.; Liu, Y. M.; Cao, Y.; He, H. Y.; Fan, K. N. Chem.;Eur. J. 2011, 17,
7172. (h) Xiao, F.; Liu, Y.; Tang, C.; Deng, G. J. Org. Lett. 2012, 14, 984.
(18) Xie, Y.; Liu, S.; Liu, Y.; Wen, Y.; Deng, G. J. Org. Lett. 2012, 14,
1692.
(19) For reviews on borrowing hydrogen or hydrogen transfer, see:
(a) Watson, A.; Williams, J. M. J. Science 2010, 329, 635. (b) Whittlesey,
M. K.; Williams, J. M. J. Dalton Trans. 2009, 5, 753. (c) Guillena, G.;
Ram oꢀ n, D. G.; Yus, M. Chem. Rev. 2010, 110, 1611.
(20) (a) Plietker, B. Iron Catalysis in Organic Chemistry: Reactions
and Applications; Wiley-VCH: Weinheim, 2008. (b) Plietker, B. Iron
Catalysis: Fundamentals and Applications; Springer: Heideberg, 2011.
(e) Chen, F.; Shen, C.; Yang, D. Tetrahedron Lett. 2011, 52, 2128.
(f) Kangani, C.; Kelley, D.; Day, B. Tetrahedron Lett. 2006, 47, 6497.
(g) Wang, Y.; Sarris, K.; Sauer, D.; Djuric, S. Tetrahedron Lett. 2006, 47,
4
823. (h) Seijas, J.; Vazquez-Tato, M.; Carballido-Reboredo, M.;
Crecente-Campo, J.; Romar-Lopez, L. Synlett 2007, 313.
11) (a) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M.
(
Org. Lett. 2003, 5, 3713. (b) Kidwai, M.; Bansal, V.; Saxena, A.; Aerryb,
S.; Mozumdar, S. Tetrahedron Lett. 2006, 47, 8049.
(
12) Chen, Y.; Qian, L.; Zhang, W.; Han, B. Angew. Chem., Int. Ed.
008, 47, 9330.
13) Blacker, A.; Farah, M.; Hall, M.; Marsden, S.; Saidi, O.;
Williams, J. M. J. Org. Lett. 2009, 11, 2039.
14) Yoo, W.; Yuan, H.; Miyamura, Kobayashi, S. Adv. Synth.
2
(
(
Catal. 2011, 353, 3085.
Org. Lett., Vol. 14, No. 11, 2012
2723

diglyme and DMF all resulted much lower yields (entries
1ꢀ13). Other solvents such as p-xylene, anisole, and
Notably, the coupling of hetero benzylic alcohols such as
2-pyridinemethanol (2k) and 3-pyridinemethanol (2l) with
1a afforded 3k and 3l in 82 and 78% yields, respectively
(entries 11 and 12). Unfortunately, aliphatic alcohols are
not suitable substrates for this kind of transformation
under the optimal conditions.
1
chlorobenzene were proven to be also good solvents for
this reaction (entries 15ꢀ17). Interestingly, slightly higher
yields were obtained when the catalyst loading was de-
creased to 3 or even 2 mol % (entries 18 and 19). The
reaction temperature is another important factor for the
yield of the product. The reaction yield decreased to 67%
when the temperature was decreased to 130 °C (entry 20).
Good yield still could be achieved when the reaction was
carried out under an atmosphere of air (entry 21).
a
Table 2. Reactions of 1a with Various Benzylic Alcohols
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst (mol %)
solvent
toluene
yield (%)
1
2
3
4
5
6
7
8
9
0
FeSO
Fe
Fe(NO
Fe (SO
4
(5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NMP
trace
trace
trace
trace
18
2
O
3
(5)
3
)
3
(5)
(5)
2
4 3
)
ferrocene (5)
Fe(acac) (5)
3
31
FeCl
FeCl
3
(5)
(5)
79
2
81
1
0
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (3)
dppf (2)
dppf (2)
dppf (2)
82
11
41
12
13
14
15
16
17
18
19
20
21
diglyme
DMF
32
33
1,4-dioxane
p-xylene
anisole
PhCl
62
76
76
77
toluene
toluene
toluene
toluene
89
89
c
67
d
75
a
Conditions: 1a (0.2 mmol), 2a (0.5 mmol), solvent (0.5 mL), 24 h,
b
c
d
1
50 °C under argon. GC yield. At 130 °C. Under air.
a
Conditions: 1a (0.2 mmol), 2 (0.5 mmol), dppf (2 mol %), 150 °C,
24 h under argon. Isolated yields based on 1a.
b
With the optimized reaction conditions established, the
scope of the reaction with respect to2-nitrophenol (1a) and
various benzylic alcohols (2) was investigated (Table 2).
The reactions with benzylic alcohols bearing electron-
donating groups (entries 2 and 3) and electron-withdraw-
ing substituents at the aromatic ring (entries 4 and 5)
proceeded smoothly to give the desired products in good
yields. Good yield was obtained when 4-bromobenzyl
alcohol (2f) was used, and the desired product was
achieved in 84% yield (entry 6). The position of the
substituents on the phenyl ring of benzyl alcohols affected
the reaction yield slightly. Good yields were obtained when
To further explore the scope of the reaction, various
2-nitrophenols were employed to react with 2a under the
optimized conditions (Table 3). A series of functional
groups including methyl, methoxy, chloro, bromo, and
fluoro were well tolerated under the optimal reaction
conditions, and the desired products were obtained in
moderate to good yields (Table 3, entries 1ꢀ8). The
position of the substituents on the phenyl ring of 2-nitro-
phenol slightly affected the reaction yield (entries 1ꢀ3).
Interestingly, the reaction of 2-aminophenol with benzyl
alcohol under optimized conditions resulted much lower
yield (entry 9).
2
2
-methylbenzyl alcohol (2g), 3-methylbenzyl alcohol (2h),
-chlorobenzyl alcohol (2i), and 1-naphthalenemethanol
(
2j) were used as starting materials (entries 7ꢀ10).
724
2
Org. Lett., Vol. 14, No. 11, 2012

a
Table 3. Reactions of 2a with Various Nitrophenols
Scheme 2. Proposed Mechanism
In summary, we have developed an iron-catalyzed 2-
arylbenzoxazole formation from o-nitrophenols and
benzylic alcohols using a hydrogen-transfer strategy.
The alcohol acted both as coupling reagent and reduc-
tant. Functional groups such as methyl, methoxy, fluoro,
chloro, and bromo were all well tolerated under the
optimized reaction conditions. The alcohol oxidation,
nitro reduction, heterocycle formation, and heterocycle
oxidation were realized in a cascade. The scope, mechan-
ism, and synthetic applications of this reaction are under
investigation.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20902076,
21172185), the Hunan Provincial Natural Science Foun-
dation of China (11JJ1003), the New Century Excellent
Talents in University from Ministry of Education of China
(NCET-11-0974), and the Scientific Research Foundation
for Returned Scholars, Ministry of Education of China
a
Conditions: 1 (0.2 mmol), 2a (0.5 mmol), dppf (2 mol %), 150 °C,
4 h under argon. Isolated yields based on 1.
b
2
A plausible mechanism to rationalize this transforma-
(2011-1568).
tion is illustrated in Scheme 2. Oxidation of 2a generates
the corresponding aldehyde D and reduces 1a to C. Con-
densation of D with C generates an intermediate imine E,
which can be in equilibrium with dihydrobenzazole F. A
second hydrogen-transfer process from F to 1a provides
the desired product 3a. In the whole process, nitro group
acts as hydrogen acceptor (oxidant) two times.
Supporting Information Available. General experimen-
tal procedure and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2725